Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old mice. None of the mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.

中文翻译：

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Col18a1 敲除小鼠作为早期脑小血管疾病模型的微血管损伤、神经炎症和细胞外基质重塑

XVIII 型胶原蛋白 (COL18) 是血管基底膜中丰富的硫酸乙酰肝素蛋白多糖。在这里，我们询问 (i) COL18 的缺失是否会导致血脑屏障 (BBB) 破坏、小动脉和毛细血管的病理改变以及脑小血管疾病 (CSVD) 中发现的神经炎症，以及 (ii) 这些变化是否会导致可能与突触和神经细胞外基质（ECM）的重塑有关。我们发现 5 个月大的小鼠深部灰质中小鼠 IgG 的 BBB 通透性升高，并且在全脑毛细血管和小动脉中观察到血管内红细胞积聚。 BBB 通透性随着年龄的增长而增加，并影响 12 个月大小鼠的皮质区域和海马体。没有一只小鼠表现出晚期脑小血管病的特征，例如出血，也没有表现出血管周围空间扩大。缺乏引起的 BBB 渗漏伴随着小胶质细胞和星形胶质细胞的激活、与快速尖峰抑制性中间神经元相关的神经周围网络 ECM 中聚集蛋白聚糖的丢失，以及突触周围 ECM 蛋白多糖短聚糖和兴奋性突触处小胶质细胞补体蛋白 C1q 的积累。作为这些调节的基础途径，我们发现通过 TGF-ß1/Smad3/TIMP-3 级联的信号传导增加。我们通过在脑高血压动脉病患者尸检大脑中证明该蛋白参与血管重塑，验证了 COL18 对 CSVD 小血管壁结构的关键作用。我们的研究强调了血管周围 ECM、细胞外蛋白水解和神经周围/突触周围 ECM 的改变之间的关联，作为 CSVD 突触和认知改变的可能底物。